Vandetanib, an Inhibitor of VEGF Receptor-2 and EGF Receptor, Suppresses Tumor Development and Improves Prognosis of Liver Cancer in Mice
Mené sur des lignées cellulaires et un modèle murin, cette étude évalue l'activité antitumorale et la toxicité du vandetanib, un composé dont le mécanisme d'action consiste à supprimer la phosphorylation des récepteurs VEGFR-2 et EGFR
Résumé en anglais
Purpose: Vascular endothelial growth factor (VEGF), epithelial growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are expressed in hepatocellular carcinoma (HCC) and play a role in its growth. Vandetanib, a multi-kinase inhibitor, suppresses the phosphorylation of VEGF receptor 2 (VEGFR-2) and EGF receptor (EGFR). The aim of this study was to clarify the anti-tumor effect of vandetanib in mouse HCC. Experimental Design:We evaluated the effects of vandetanib on proliferation of human umbilical vein cells (HUVEC) and three hepatoma cell lines as well as the phosphorylation of VEGFR-2 and EGFR in these cells. Mice were implanted with hepatoma cells subcutaneously or orthotopically in the liver, and treated with 50 or 75 mg/kg vandetanib. We analyzed the effects of treatment on tumor cell proliferation and apoptosis, vessel density, phosphorylation of VEGFR-2 and EGFR, production of VEGF, TGF-alpha and EGF in tumor tissues. Adverse events on vandetanib administration were also investigated. Results:Vandetanib suppressed phosphorylation of VEGFR-2 in HUVEC and EGFR in hepatoma cells and inhibited cell proliferation. In tumor-bearing mice, vandetanib suppressed phosphorylation of VEGFR-2 and EGFR in tumor tissues, significantly reduced tumor vessel density, enhanced tumor cell apoptosis, suppressed tumor growth, improved survival, reduced number of intrahepatic metastases, and up-regulated VEGF, TGF-alpha and EGF in tumor tissues. Treatment with vandetanib was not associated with serious adverse events, including ALT abnormality, bone marrow suppression or body weight loss. Conclusions:The anti-tumor effects of vandetanib in mice suggest it is a potentially suitable and safe chemotherapeutic agent for HCC.
